This invention pertains to an osmotic device containing pseudoephedrine and an H1 antagonist, or antihistamine. More particularly, it pertains to an osmotic device tablet, which provides a controlled release of pseudoephedrine and a rapid or immediate release of an H1 antagonist.
Antihistamines, such as H1 antagonists, are used to treat seasonal allergic rhinitis (SAR); however, antihistamines do not effectively treat nasal congestion, e.g., stuffed or blocked nasal passages. Pseudoephedrine (Ps, a nasal decongestant) is widely used for the treatment of nasal congestion and other related diseases or disorders; however, it does not effectively treat SAR. Therefore, antihistamine/nasal decongestant combinations are frequently used to more effectively treat SAR.
The antihistamine and nasal decongestant can be administered in single or multiple dosage forms. Single dosage unit combination dosage forms containing a combination of Ps with an H1 antagonist, such as loratadine, cetirizine, fexofenadine, terfenadine, acrivastine or astemizole, are known. These combination tablet dosage forms generally provide a rapid release of the antihistamine and a controlled release of Ps. For example, Allegra-D(trademark), Claritin-D(trademark), Claritin-D(trademark) 24-Hour, Seldane-D(trademark) and Semprex-D(trademark) (capsule) dosage forms are commercially available products that provide a rapid release of an H1 antagonist and a controlled or sustained release of Ps. These tablets are generally made for once- or twice-daily administration. U.S. Pat. No. 6,051,585 to Weinstein et al. discloses a combination formulation containing pseudoephedrine, with limited duration of action, and an antihistamine for treating SAR.
Applicant""s note that Hoechst Marion Roussel has attempted unsuccessfully to develop sustained release osmotic device product that provides therapeutic blood plasma levels of PS and FEX over a 24 hour period.
Sussman et al. (J. Allergy Clin. Immunol. (1999 July), 104(1), pp. 100-106) have reported on the evaluation of the twice daily combined administration of fexofenadine and pseudoephedrine using two separate dosage forms: an immediate release form containing 60 mg of FEX and a sustained release form containing 120 mg of PS.
Fexofenadine (terfenadine carboxylate) and derivatives are known for the treatment of SAR. U.S. Pat. No. 4,254,129 to Carr et al., No. 5,375,693 to Woosley et al., No. 5,578,610 to D""Ambra, and No. 6,037,353 disclose the use of fexofenadine and related compounds in treating SAR.
Osmotic devices and other tablet formulations are known for their ability to provide a controlled release of a wide range of drugs. Such osmotic devices and other tablet formulations are disclosed in U.S. Pat. No. 4,014,334 to Theeuwes et al., U.S. Pat. No. 4,576,604 to Guittard et al., Argentina Patent No. 234,493, U.S. Pat. No. 4,673,405 to Guittard et al., U.S. Pat. No. 5,558,879 to Chen et al., U.S. Pat. No. 4,810,502 to Ayer et al., U.S. Pat. No. 4,801,461 to Hamel et al., U.S. Pat. No. 5,681,584 to Savastano et al., U.S. Pat. No. 3,845,770, U.S. Pat. No. 4,008,719 to Theeuwes et al., U.S. Pat. No. 4,058,122 to Theeuwes et al., U.S. Pat. No. 4,116,241 to Theeuwes et al., U.S. Pat. No. 4,160,452 to Theeuwes, U.S. Pat. No. 4,256,108 to Theeuwes, and Argentina Patent No. 199,301, the entire disclosures of which are hereby incorporated by reference. In particular, tablet formulations for providing antihistamines are disclosed in U.S. Pat. No. 4,650,807 to Findlay et al., and U.S. Pat. No. 4,501,893 to Findlay et al., the entire disclosures of which are hereby incorporated by reference.
While conventional sustained release dosage forms, such as described above, are effective, osmotic devices such as those described by Faour et al. (U.S. Pat. No. 6,004,582), the entire disclosure of which is hereby incorporated by reference, are particularly advantageous for delivering two different dosage forms from a single osmotic device tablet. While Faour et al. disclose osmotic device formulations comprising slow release pseudoephedrine with rapid release loratadine and slow release pseudoephedrine with rapid release astemizol, they do not disclose osmotic devices that provide the specific formulations, plasma profiles or release profiles for the various different combinations claimed herein, nor osmotic devices having a drug-containing external coat that has been spray coated rather than compression coated onto the device.
In one aspect, the present invention provides an osmotic device comprising:
a core comprising a therapeutically effective amount of pseudoephedrine (PS) and at least one osmotic agent or osmopolymer, wherein the core provides a controlled release of pseudoephedrine;
a semipermeable membrane surrounding the core and having a passageway there through; and
an external coat comprising a therapeutically effective amount of an H1 antagonist, wherein the external coat provides a rapid release of the H1 antagonist; wherein:
at least 67% of the pseudoephedrine is released within 23 hours, and at least 65% of the H1 antagonist is released within 40 minutes after exposure of the osmotic device to an aqueous solution.
In some embodiments, the H1 antagonist is selected from the group consisting of acrivastine, astemizol, azelastine, cetirizine, ebastine, epinastine, fexofenadine, loratadine, mizolastine, norastemizol, prometazine and terfenadine.
In other embodiments, the external coat is applied by spray coating rather than by compression coating. By spray coating rather than compression coating the external coat is thinner, and therefore a smaller osmotic device is formed.
Other embodiments include those wherein: 1) at least 75% of the H1 antagonist is released within 30 min after administration; 2) at least 75% of the H1 antagonist is released in 20 min after administration; 3) at least 75% of the H1 antagonist is released within 10 min after administration; 4) at least 75% of the H1 antagonist is released within 5 min after administration; 5) all of the H1 antagonist is released within 90 min after administration; 6) all of the H1 antagonist is released within 45 min after administration; 7) all of the H1 antagonist is released within 30 min after administration; 8) all of the H1 antagonist is released within 20 min after administration; 9) all of the H1 antagonist is released within 10 min after administration; 10) all of the H1 antagonist is released within 5 min after administration; 11) the osmotic device further comprises an inert and erodible water soluble lamina interposed the semipermeable membrane and the drug-containing outer coating; 12) the water soluble lamina comprises poly(vinylpyrrolidone)-(vinyl acetate) copolymer; 13) all of the H1 antagonist is released within 120 min after administration; and/or 14) all of the H1 antagonist is released within 180 min after administration.
Still other embodiments include those wherein: 1) 10-25% of the PS is released within 3 hours after administration; 2) 25-50% of the PS is released within 7 hours after administration; 3) 50-66% of the PS is released within 11 hours after administration; 4) 66-79% of the PS is released within 15 hours after administration; and 5) 79-100% of the PS is released within 23 hours after administration or 79-90% of the PS is released within 23 hours after administration. Generally, all of the PS is released within 24 hours min after administration.
Another embodiment includes one wherein: 1) 5-23% of the PS is released within 3 hours after administration; 2) 20-52% of the PS is released within 7 hours after administration; 3) 36-72% of the PS is released within 11 hours after administration; 4) 53-82% of the PS is released within 15 hours after administration; and 5) 67-100% of the PS is released within 23 hours after administration.
More embodiments include those wherein: 1) 8-12% of the PS is released within 3 hours after administration; 2) 25-32% of the PS is released within 7 hours after administration; 3) 42-52% of the PS is released within 11 hours after administration; 4) 55-70% of the PS is released within 15 hours after administration; and 5) at least 75% of the PS is released within 23 hours after administration or 75-100% of the PS is released within 23 hours after administration.
Even other embodiments of the invention include those wherein: 1) 9-11% of the PS is released within 3 hours; 2) 19-22% of the PS is released within 5 hours; 3) 28-31% of the PS is released within 7 hours; 4) 35-40% of the PS is released within 9 hours; 5) 45-50% of the PS is released within 11 hours; 6) 50-55% of the PS is released within 13 hours; 7) 60-65% of the PS is released within 15 hours; and 8) at least 67% of the PS is released within 23 hours after exposure to an aqueous environment.
Yet another embodiment of the invention includes one wherein: 1) 5-23% of the PS is released within 3 hours; 2) 12-38% of the PS is released within 5 hours; 3) 20-52% of the PS is released within 7 hours; 4) 28-62% of the PS is released within 9 hours; 5) 36-72% of the PS is released within 11 hours; 6) 44-77% of the PS is released within 13 hours; 7) 53-82% of the PS is released within 15 hours; and 8) at least 67% of the PS is released within 23 hours after exposure to an aqueous environment.
Still yet another embodiment of the invention includes an osmotic device wherein: 1) 5-23% of the PS is released within 3 hours; 2) 20-52% of the PS is released within 7 hours; 3) 36-72% of the PS is released within 11 hours; 4) 53-82% of the PS is released within 15 hours; and 5) at least 67% of the PS is released within 23 hours after exposure to an aqueous environment.
Yet other embodiments includes those wherein the PS is released at a zero order or pseudo-zero order rate for a period of at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours and at least 20 hours.
Another aspect of the invention provides a method of treating a respiratory congestion related disorder, such as nasal congestion, or an allergy related disorder, such as allergic rhinitis, in a mammal. The method comprises the step of administering an osmotic device, which provides a controlled release of pseudoephedrine from its core and a rapid release of an H1 antagonist from an external coat, wherein at least 75% of the H1 antagonist is released within about 40 minutes and at least about 67% of the pseudoephedrine is released within about 23 hours.
In other embodiments, the osmotic device has a pseudoephedrine release profile similar to that shown in FIG. 1 or 2.
Target therapeutic levels for the H1 antagonist are in the range of about 2 ng to about 700 ng per ml of plasma.
Target therapeutic levels for the pseudoephedrine are generally in the range of about 3 ng to about 1000 ng per ml of plasma.
The osmotic device generally delivers the H1 antagonist to the upper GI tract and the pseudoephedrine to the middle to lower GI tract.
Another aspect of the invention provides an osmotic device comprising:
(a) a core comprising a therapeutically effective amount of pseudoephedrine which is delivered at a controlled rate over a period of about 18-24 hours;
(b) a semipermeable membrane surrounding the core and a passageway through the semipermeable membrane;
(c) an inert water soluble coating surrounding the semipermeable membrane and plugging the passageway; and
(d) a fexofenadine-containing water soluble coating surrounding the inert coating for delivering a therapeutically effective amount of fexofenadine at a rapid rate over a period of less than about 90 min.
Some specific embodiments of the invention also include those wherein the drug-containing water soluble coating is present in an amount of about 1-90% wt., 9-40% wt., at least about 25% wt., about 25-40% wt. or about 30-40% wt. based upon the total weight of the osmotic device.
Other features, advantages and embodiments of the invention will become apparent to those skilled in the art by the following description, accompanying examples.